F/G Region Rigidity is Inversely Correlated to Substrate Promiscuity of Human CYP Isoforms Involved in Metabolism

Becker, Daniel P.; Bharatam, Prasad V.; Gohlke, Holger

doi:10.1021/acs.jcim.1c00558

Cited by 10 publications

(26 citation statements)

References 80 publications

(121 reference statements)

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“…72 Existing public data sets from previous experiments present an facile opportunity in this regard. 1,2,26,27,94…”

Section: Discussionmentioning

confidence: 99%

“…5B). This can be illustrated by two case studies that relate conflicting accounts of the role of flexibility in enzyme promiscuity: Flexibility and promiscuity are correlated in a group of 57 human cytochrome P450 (CYT) enzymes, 106 while the opposite trend is observed in a group of 147 esterases. 67 In the case of CYT, we know that the binding pocket is quite small (Δ θ 0 < 0), so we can infer that the proteins fall to the right of the optimal line (bottom purple arrow, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…93 Existing public data sets from previous experiments present a facile opportunity in this regard. 1,2,29,30,106 Molecular discrimination by aminoacyl-tRNA syn-thetases. To evaluate the theory that protein size depends on task di culty, we need to know both the relevant non-cognate ligands and necessary binding specicity.…”

Section: Examiningmentioning

confidence: 99%

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General theory of specific binding: insights from a genetic-mechano-chemical protein model

McBride

Eckmann

Tlusty³

2022

Preprint

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Proteins need to selectively interact with specific targets among a multitude of similar molecules in the cell. Despite a firm physical understanding of binding interactions, we lack a general theory of how proteins evolve high specificity. Here, we present a model that combines chemistry, mechanics and genetics, and explains how their interplay governs the evolution of specific protein-ligand interactions. The model shows that there are many routes to achieving discrimination -- by varying degrees of flexibility and shape/chemistry complementarity -- but the key ingredient is precision. Harder discrimination tasks require more collective and precise coaction of structure, forces and movements. Proteins can achieve this through correlated mutations extending far from a binding site, which fine tune the localized interaction with the ligand. Thus, the solution of more complicated tasks is aided by increasing the protein, and proteins become more evolvable and robust when they are larger than the bare minimum required for discrimination. Our model makes testable, specific predictions about the role of flexibility in discrimination, and how to independently tune affinity and specificity. Thus, the proposed theory of molecular discrimination addresses the natural question ``why are proteins so big?'' A possible answer is that molecular discrimination is often a hard task best performed by adding more layers to the protein.

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“…72 Existing public data sets from previous experiments present an facile opportunity in this regard. 1,2,26,27,94…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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General theory of specific binding: insights from a genetic-mechano-chemical protein model

McBride

Eckmann

Tlusty³

2022

Preprint

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show abstract

“…5D). This can be illustrated by two case studies that relate con icting accounts of the role of exibility in enzyme promiscuity: Flexibility and promiscuity are correlated in a group of 57 human cytochrome P450 (CYT) enzymes, 94 while the opposite trend is observed in a group of 147 esterases. 95 In the case of CYT, we know that the binding pocket is quite small (Δ𝜃 0 < 0), so we can infer that the proteins fall to the right of the optimal line (bottom purple arrow, Fig.…”

Section: Molecular Discrimination By a Hypothetical Mechano-chemical ...mentioning

confidence: 99%

“…72 Existing public data sets from previous experiments present an facile opportunity in this regard. 1,2,26,27,94 Molecular discrimination by aminoacyl-tRNA synthetases. To evaluate the theory that protein size depends on task di culty, we need to know both the relevant non-cognate ligands and necessary binding speci city.…”

Section: Molecular Discrimination By a Hypothetical Mechano-chemical ...mentioning

confidence: 99%

General theory of specific binding: insights from a genetic-mechano-chemical protein model

McBride¹,

Eckmann²,

Tlusty³

2022

Preprint

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Proteins need to selectively interact with speci c targets among a multitude of similar molecules in the cell. Despite a rm physical understanding of binding interactions, we lack a general theory of how proteins evolve high speci city. Here, we present a model that combines chemistry, mechanics and genetics, and explains how their interplay governs the evolution of speci c protein-ligand interactions. The model shows that there are many routes to achieving discrimination -by varying degrees of exibility and shape/chemistry complementarity -but the key ingredient is precision. Harder discrimination tasks require more collective and precise coaction of structure, forces and movements. Proteins can achieve this through correlated mutations extending far from a binding site, which ne tune the localized interaction with the ligand. Thus, the solution of more complicated tasks is aided by increasing the protein, and proteins become more evolvable and robust when they are larger than the bare minimum required for discrimination. Our model makes testable, speci c predictions about the role of exibility in discrimination, and how to independently tune a nity and speci city. Thus, the proposed theory of molecular discrimination addresses the natural question "why are proteins so big?" A possible answer is that molecular discrimination is often a hard task best performed by adding more layers to the protein.Significance statement. Proteins excel at discriminating between molecules. Otherwise, cells would not be able to accurately translate mRNA into protein sequences, chemical signals would get mixed up, and enzymes would catalyze unwanted interactions. To understand how proteins can achieve this, we develop a model of protein binding to study evolution of molecular discrimination through the interplay of shape, exibility, chemical binding and entropy. The model reveals that mutations far from the binding site can ne-tune binding interactions, and larger proteins are better discriminators. Proteins thus solve the discrimination problem by being large so that they have many ways of ne-tuning binding.

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A comparative electronic structure analysis of reactive metabolites of oxicams

Burman,

Manchanda,

Bhakhar

et al. 2024

Computational and Theoretical Chemistry

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F/G Region Rigidity is Inversely Correlated to Substrate Promiscuity of Human CYP Isoforms Involved in Metabolism

Cited by 10 publications

References 80 publications

General theory of specific binding: insights from a genetic-mechano-chemical protein model

General theory of specific binding: insights from a genetic-mechano-chemical protein model

General theory of specific binding: insights from a genetic-mechano-chemical protein model

A comparative electronic structure analysis of reactive metabolites of oxicams

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